IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT

TY - JOUR

T1 - IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT

AU - Röhrich, Manuel

AU - Loktev, Anastasia

AU - Wefers, Annika K

AU - Altmann, Annette

AU - Paech, Daniel

AU - Adeberg, Sebastian

AU - Windisch, Paul

AU - Hielscher, Thomas

AU - Flechsig, Paul

AU - Floca, Ralf

AU - Leitz, Dominik

AU - Schuster, Julius P

AU - Huber, Peter E

AU - Debus, Jürgen

AU - von Deimling, Andreas

AU - Lindner, Thomas

AU - Haberkorn, Uwe

PY - 2019/11

Y1 - 2019/11

N2 - PURPOSE: Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used 68Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas).METHODS: For binding studies with 177Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with 68Ga-labeled compounds followed by small-animal PET imaging and 177Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of 68Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody.RESULTS: FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma.CONCLUSIONS: Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.

AB - PURPOSE: Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used 68Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas).METHODS: For binding studies with 177Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with 68Ga-labeled compounds followed by small-animal PET imaging and 177Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of 68Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody.RESULTS: FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma.CONCLUSIONS: Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.

KW - Acebutolol

KW - Adult

KW - Animals

KW - Biological Transport

KW - Brain Neoplasms/diagnostic imaging

KW - Cell Line, Tumor

KW - Female

KW - Gelatinases/metabolism

KW - Glioblastoma/diagnostic imaging

KW - Humans

KW - Isocitrate Dehydrogenase/genetics

KW - Ligands

KW - Membrane Proteins/metabolism

KW - Mice

KW - Middle Aged

KW - Mutation

KW - Naphthols

KW - Neoplasm Grading

KW - Positron Emission Tomography Computed Tomography

KW - Radioactive Tracers

KW - Serine Endopeptidases/metabolism

KW - Triazines

KW - Young Adult

U2 - 10.1007/s00259-019-04444-y

DO - 10.1007/s00259-019-04444-y

M3 - SCORING: Journal article

C2 - 31388723

VL - 46

SP - 2569

EP - 2580

JO - EUR J NUCL MED MOL I

JF - EUR J NUCL MED MOL I

SN - 1619-7070

IS - 12

ER -